DESCRIPTION: (provided by the applicant): Filarial parasites infect a wide variety of vertebrate hosts, including man. Considerable morbidity results fr6m filarial infections such as lymphatic filariaisis (elephantiasis) and onchocerciasis (river blindness). These parasitic nematodes display complex life cycles, requiring arthropod vectors for development and transmission to new hosts. In the vertebrate host, the parasite reproduces sexually, giving rise to first stage larvae that migrate through host tissues or blood. These first stage larvae, or microfilariae, must be ingested by feeding vectors, which support their further development, for transmission to occur. This application proposes to investigate several aspects of filarial reproduction and larval development that may serve as therapeutic targets. Chitin synthesis has long been known to be required for nematode eggshell formation. We have recently cloned the genes for chitin synthase from two different filarial parasites, and demonstrated expression in oocytes and early embryos. We will investigate the regulation of chitin synthesis during the transition from ooctye to fertilized zygote, as well as the role of chitin metabolism in subsequent embryonic growth. We will also investigate the role of chitin synthase in later larval stages and in adult somatic tissues, to understand if this enzyme may be a protective antigen. The relationship between chitin synthesis and development of a functional gut will be determined. Methods for posttranscriptional gene silencing (RNA interference) will be developed to study the loss-of-function phenotype for genes involved in chitin metabolism.